Nasal devices

ABSTRACT

A nasal delivery device ( 11 ) for delivering substance to a nasal airway ( 1 ) of a subject, comprising: first and second nosepiece units ( 17, 19 ), each including a nosepiece ( 21, 23 ) for fitting to respective nostrils of a subject; at least one substance supply unit ( 13, 15 ) for supplying substance for delivery to the nasal airway ( 1 ) of the subject; and a valve unit ( 35, 37 ) for selectively fluidly connecting the at least one substance supply unit ( 13, 15 ) alternately to respective ones of the nosepiece units ( 17, 19 ).

The present invention relates to a nasal delivery device for and amethod of delivering substance, in particular one of a liquid, as asuspension or solution, or a powder containing a medicament, especiallysystemic or topical pharmaceuticals, or a vaccine to the nasal airway ofa subject.

Referring to FIG. 1, the nasal airway 1 comprises the two nasal cavities2, 3 separated by the nasal septum 4, which airway 1 includes numerousostia, such as the paranasal sinus ostia 5 connected to the paranasalsinuses 6 and the tubal ostia 7 connected to the tuba auditiva 8 and themiddle ears 9, and olfactory cells, and is lined by the nasal mucosa.The nasal airway 1 can communicate with the nasopharynx, the oral cavityand the lower airway, with the nasal airway 1 being in selectivecommunication with the anterior region of the nasopharynx and the oralcavity by opening and closing of the oropharyngeal velum.

There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Other nasalconditions include nasal polyps which arise from the paranasal sinuses,hypertrophic adenoids, secretory otitis media, sinus disease and reducedolfaction.

In the treatment of certain nasal conditions, the topical administrationof medicaments is preferable, particularly where the nasal mucosa is theprime pathological pathway, such as in treating or relieving nasalcongestion. Medicaments that are commonly topically delivered includedecongestants, anti-histamines, cromoglycates, steroids and antibiotics.At present, among the known anti-inflammatory pharmaceuticals, topicalsteroids have been shown to have an effect on nasal congestion. Topicaldecongestants have also been suggested for use in relieving nasalcongestion. The treatment of hypertrophic adenoids and chronic secretoryotitis media using topical decongestants, steroids and anti-microbialagents, although somewhat controversial, has also been proposed.Further, the topical administration of pharmaceuticals has been used totreat or at least relieve symptoms of inflammation in the anteriorregion of the nasopharynx, the paranasal sinuses and the auditory tubes.

Medicaments can also be systemically delivered through the nasalpathway, the nasal pathway offering a good administration route for thesystemic delivery of pharmaceuticals, such as hormones, for example,oxytocin and calcitionin, and analgetics, such as anti-migrainecompositions, as the high blood flow and large surface area of the nasalmucosa advantageously provides for rapid systemic uptake.

Nasal delivery is also expected to be advantageous for theadministration of medicaments requiring a rapid onset of action, forexample, analgetics, anti-emetics, insulin, anti-epileptics, sedativesand hypnotica, and also other pharmaceuticals, for example,cardio-vascular drugs. It is envisaged that nasal administration willprovide for a fast onset of action, at a rate similar to that ofinjection and at a rate much faster than that of oral administration.Indeed, for the treatment of many acute conditions, nasal administrationis advantageous over oral administration, since gastric stasis canfurther slow the onset of action following oral administration.

It is also expected that nasal delivery could provide an effectivedelivery route for the administration of proteins and peptides asproduced by modem biotechnological techniques. For such substances, themetabolism in the intestines and the first-pass-effect in the liverrepresent significant obstacles for reliable and cost-efficientdelivery.

Furthermore, it is expected that nasal delivery using the nasal deliverytechnique of the present invention will prove effective in the treatmentof many common neurological diseases, such as Alzheimer's, Parkinson's,psychiatric diseases and intracerebral infections, where not possibleusing existing techniques. The nasal delivery technique of the presentinvention allows for delivery to the olfactory region, which region islocated in the superior region of the nasal cavities and represents theonly region where it is possible to circumvent the blood-to-brainbarrier (BBB) and enable communication with the cerebrospinal fluid(CSF) and the brain.

Also, it is expected that the nasal delivery technique of the presentinvention will allow for the effective delivery of vaccines.

Aside from the delivery of medicaments and vaccines, the irrigation ofthe nasal mucosa with liquids, in particular saline solutions, iscommonly practised to remove particles and secretions, as well as toimprove the mucociliary activity of the nasal mucosa. These solutionscan be used in combination with active pharmaceuticals.

For any kind of drug delivery, accurate and reliable dosing isessential, but it is of particular importance in relation to theadministration of potent drugs which have a narrow therapeutic window,drugs with potentially serious adverse effects and drugs for thetreatment of serious and life-threatening conditions. For someconditions, it is essential to individualize the dosage to theparticular situation, for example, in the case of diabetes mellitus. Fordiabetes, and, indeed, for many other conditions, the dosage of thepharmaceutical is preferably based on actual real-time measurements.Currently, blood samples are most frequently used, but the analysis ofmolecules in the exhalation breath of subjects has been proposed as analternative to blood analysis for several conditions. Breath analysis iscurrently used for the diagnosis of conditions such as helicobacterpylori infections which cause gastric ulcers.

WO-A-00/51672 discloses a delivery device for delivering substance, inparticular a medicament, in a bi-directional flow through the nasalcavities, that is, an air flow which passes into one nostril, around theposterior margin of the nasal septum and in the opposite direction outof the other nostril. This bi-directional air flow advantageously actsto stimulate the sensory nerves in the nasal mucosa, therebyconditioning the subject for the delivery and providing a morecomfortable delivery situation.

It is an aim of the present invention to provide an improved nasaldelivery device for and method of delivering substance to the nasalairway of a subject.

In one aspect the present invention provides a nasal delivery device fordelivering substance to a nasal airway of a subject, comprising: firstand second nosepiece units, each including a nosepiece for fitting torespective nostrils of a subject; at least one substance supply unit forsupplying substance for delivery to the nasal airway of the subject; anda valve unit for selectively fluidly connecting the at least onesubstance supply unit alternately to respective ones of the nosepieceunits.

Preferably, the delivery device further comprises: a mouthpiece throughwhich the subject in use exhales.

Preferably, the delivery device further comprises: a gas supply channelfor supplying a gas flow for entraining substance supplied by the atleast one substance supply unit.

In one embodiment the mouthpiece is fluidly connected to the gas supplychannel, whereby the gas flow is an air flow developed by an exhalationbreath of the subject.

In another embodiment the delivery device further comprises: a gassupply unit which is fluidly connected to the gas supply channel fordelivering a gas flow through the gas supply channel.

Preferably, the gas supply unit is an exhalation breath actuatable unitwhich is fluidly connected to the mouthpiece such as to be actuated onexhalation by the subject.

In one embodiment the valve unit is configured alternately fluidly toconnect one of the nosepiece units to the at least one substance supplyunit and vent the other of the nosepiece units, such that, where the gasflow is at a driving pressure which is such as to cause the gas flow toflow around the posterior margin of the nasal septum and through thenasal airway, the gas flow delivered through the one nosepiece unit isvented through the other nosepiece unit.

Preferably, the delivery device further comprises: at least one flowresistor to which the other nosepiece unit is vented.

In one embodiment the at least one flow resistor has a fixed flowresistance for providing a fixed flow resistance to the gas flow.

In another embodiment the at least one flow resistor is a progressiveresistor for progressively providing an increasing flow resistance tothe gas flow.

Preferably, the progressive resistor comprises an expandable memberwhich provides a progressively increasing resistance to the gas flow.

Preferably, the delivery device further comprises: a control unit forcontrolling the valve unit such as to provide for alternate delivery ofsubstance through respective ones of the first and second nosepieceunits.

In one embodiment the delivery device comprises: a single substancesupply unit for supplying substance for delivery alternately torespective ones of the first and second nosepiece units.

In another embodiment the delivery device comprises: first and secondsubstance supply units for supplying substance for delivery torespective ones of the first and second nosepiece units.

Preferably, the valve unit comprises first and second valves, each beingfluidly connected to a respective one of the first and second nosepieceunits.

In another aspect the present invention provides a method of deliveringsubstance to a nasal airway of a subject, comprising the steps of:fitting first and second nosepiece units to respective nostrils of asubject; and delivering substance alternately through respective ones ofthe nosepiece units.

Preferably, the method further comprises the step of: exhaling through amouthpiece during delivery of substance.

Preferably, substance is delivered in a gas flow.

In one embodiment the gas flow is an air flow developed by an exhalationbreath of the subject.

In another embodiment the gas flow is a gas flow separate to anexhalation breath of the subject.

In one embodiment substance is delivered alternately through thenosepiece units and the other of the nosepiece units is vented, suchthat, where the gas flow is at a driving pressure which is such as tocause the gas flow to flow around the posterior margin of the nasalseptum and through the nasal airway, the gas flow delivered through theone nosepiece unit is vented through the other nosepiece unit.

Preferably, the gas flow is vented through a flow resistor.

In one embodiment the flow resistor has a fixed flow resistance andprovides a fixed flow resistance to the gas flow.

In another embodiment the flow resistor is a progressive resistor whichprovides a progressively increasing flow resistance to the gas flow.

Preferably, the progressive resistor comprises an expandable memberwhich provides a progressively increasing resistance to the gas flow.

In one embodiment substance is supplied from a single substance supplyunit.

In another embodiment substance is supplied to the first and secondnosepiece units from respective ones of first and second substancesupply units.

In a further aspect the present invention provides a nasal deliverydevice for delivering substance to a nasal airway of a subject,comprising: at least one delivery unit for delivering substance to anasal airway of a subject; and a gas supply unit for applying a varyingpressure in the nasal airway of the subject.

Preferably, the gas supply unit is configured to cycle the pressure inthe nasal airway of the subject.

More preferably, the gas supply unit is configured to provide analternating pressure in the nasal airway of the subject.

Preferably, the delivery device further comprises: a mouthpiece throughwhich the subject in use exhales.

More preferably, the gas supply unit is an exhalation breath actuatableunit which is fluidly connected to the mouthpiece such as to be actuatedon exhalation by the subject.

In yet another aspect the present invention provides a method ofdelivering substance to a nasal airway of a subject, comprising thesteps of: delivering substance to a nasal airway of a subject; andapplying a varying pressure in the nasal airway of the subject.

Preferably, the step of applying a varying pressure in the nasal airwayof the subject comprises the step of: cycling the pressure in the nasalairway of the subject.

More preferably, the step of applying a varying pressure in the nasalairway of the subject comprises the step of: alternating the pressure inthe nasal airway of the subject.

Preferably, the method further comprises the step of: exhaling through amouthpiece during delivery of substance.

In a yet further aspect the present invention provides a nasal deliverydevice for delivering substance to a nasal airway of a subject,comprising: at least one delivery unit for delivering substance to anasal airway of a subject; and a gas supply unit for alternatelydelivering and withdrawing a volume of gas through the nasal airway ofthe subject such as to cause entrained substance to be flushed inalternate directions therethrough.

Preferably, the delivery device further comprises: a mouthpiece throughwhich the subject in use exhales.

In still yet another aspect the present invention provides a method ofdelivering substance to a nasal airway of a subject, comprising thesteps of: delivering substance to a nasal airway of a subject; andalternately delivering and withdrawing a volume of gas through the nasalairway of the subject such as to cause entrained substance to be flushedin alternate directions therethrough.

Preferably, the method further comprises the step of: exhaling through amouthpiece during delivery of substance.

In a still yet further aspect the present invention provides aninterface member for attachment to a nasal delivery device, comprising,as an integral element, at least one nosepiece for fitting to a nostrilof a subject and a mouthpiece through which the subject in use exhales.

Preferably, the interface member comprises first and second nosepiecesfor fitting to respective nostrils of a subject

Preferably, the interface member is a disposable element.

In one embodiment the mouthpiece comprises a tubular section throughwhich the subject in use exhales.

In another embodiment the mouthpiece includes a flexible member which isdeflectable on exhalation into the mouthpiece.

Preferably, the mouthpiece comprises a cavity into which the subject inuse exhales, with a part of the cavity being defined by the flexiblemember.

Preferably, the flexible member comprises a resilient member.

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 schematically illustrates the nasal airway of a human subject;

FIG. 2(a) schematically illustrates a nasal delivery device inaccordance with a first embodiment of the present invention;

FIG. 2(b) illustrates the nasal delivery device of FIG. 2(a) in a first,delivery configuration;

FIG. 2(c) illustrates the nasal delivery device of FIG. 2(a) in asecond, delivery configuration;

FIG. 3(a) schematically illustrates a nasal delivery device inaccordance with a second embodiment of the present invention;

FIG. 3(b) illustrates the nasal delivery device of FIG. 3(a) in a first,delivery configuration;

FIG. 3(c) illustrates the nasal delivery device of FIG. 3(a) in asecond, delivery configuration;

FIG. 4(a) schematically illustrates a nasal delivery device inaccordance with a third embodiment of the present invention;

FIG. 4(b) illustrates the nasal delivery device of FIG. 4(a) in a first,delivery configuration;

FIG. 4(c) illustrates the nasal delivery device of FIG. 4(a) in asecond, delivery configuration;

FIG. 5(a) schematically illustrates a nasal delivery device inaccordance with a fourth embodiment of the present invention;

FIG. 5(b) illustrates the nasal delivery device of FIG. 5(a) in a first,delivery configuration; and

FIG. 5(c) illustrates the nasal delivery device of FIG. 5(a) in asecond, delivery configuration.

FIGS. 2(a) to (c) illustrate a nasal delivery device 11 in accordancewith a first embodiment of the present invention.

The delivery device 11 comprises first and second substance supply units13, 15 for supplying metered doses of substance. In preferredembodiments the substance comprises a medicament, especially systemic ortopical pharmaceuticals, or a vaccine.

In this embodiment the substance supply units 13, 15 comprise aerosolcanisters for delivering metered volumes of a propellant, preferably ahydrofluoroalkane (HFA) propellant or the like, containing substance,either as a suspension or solution.

Each of the substance supply units 13, 15 is primeable, in thisembodiment by loading a biasing element, and includes a releasemechanism, in this embodiment electrically-operated, which, whentriggered, releases the biasing element and actuates the respectivesubstance supply unit 13, 15 to deliver a metered dose of substance.

In an alternative embodiment the substance supply units 13, 15 couldcomprise mechanical delivery pumps, in particular liquid delivery pumpsor powder delivery pumps, which deliver metered doses of substance onactuation thereof.

In another alternative embodiment the substance supply units 13, 15could comprise dry powder delivery units which deliver metered doses ofsubstance, as a dry powder, on actuation thereof.

In yet another alternative embodiment the substance supply units 13, 15could comprise nebulizers which deliver metered doses of substance, asan aerosol spray, on actuation thereof.

The delivery device 11 further comprises first and second nosepieceunits 17, 19 for fitting to respective ones of the nostrils of a subjectwhich are fluidly connected to respective ones of the first and secondsubstance supply units 13, 15. In this embodiment the nosepiece units17, 19 each comprise a nosepiece 21, 23 for fitting to respective onesof the nostrils of a subject and a flow channel 25, 27 which fluidlyconnects the respective ones of the nosepieces 21, 23 and the substancesupply units 13, 15. In this embodiment the nosepieces 21, 23 arereplaceable elements.

The delivery device 11 further comprises a mouthpiece 31 which isgripped by the lips of a subject and through which the subject exhales.In this embodiment the mouthpiece 31 is a replaceable element. In apreferred embodiment the nosepieces 21, 23 and the mouthpiece 31 areintegrally formed as a single element such as to allow for replacementafter use. In this way, the delivery device 11 can be used to deliversubstance to many different subjects and yet avoid cross-contaminationfrom subject to subject.

The delivery device 11 further comprises a gas supply channel 33 whichis fluidly connected to the mouthpiece 31.

The delivery device 11 further comprises a valve unit which comprisesfirst and second valves 35, 37 which are disposed in respective ones ofthe flow channels 25, 27 of the first and second nosepiece units 17, 19and fluidly connected to the gas supply channel 33 such as to providefor the selective communication of one of the nosepieces 21, 23 with themouthpiece 31 and the respective one of the substance supply units 13,15, and the venting of the other of the nosepieces 21, 23 to atmosphere.In this embodiment the valves 35, 37 are electrically-operated valves.

Each of the valves 35, 37 comprises a first port which is fluidlyconnected to the respective nosepiece 21, 23, a second port which isfluidly connected to the respective substance supply unit 13, 15, athird port which is fluidly connected to the gas supply channel 33, anda fourth port which vents to atmosphere. Each of the valves 35, 37 isoperable between a first, delivery position in which the first, secondand third ports thereof are open and the fourth port thereof is closed,whereby substance can be delivered by the respective substance supplyunit 13, 15 and entrained by the exhalation breath of a subject, and asecond, venting position in which the first, second and fourth portsthereof are open and the third port thereof is closed, whereby theexhalation breath of a subject which has been driven through the nasalairway 1 of the subject is vented to atmosphere.

The delivery device 11 further comprises first and second flow resistorunits 39, 41 for providing a flow resistance to vented air flow whichare fluidly connected to respective ones of the fourth ports of thevalves 35, 37. In one embodiment the flow resistor units 39, 41 can eachinclude a filter for preventing the escape of substance.

In this embodiment the flow resistor units 39, 41 each include a flowresistor of fixed flow resistance for providing a fixed flow resistanceto vented air flow.

In another embodiment the flow resistor units 39, 41 could include aprogressive flow resistor for providing a progressively increasing flowresistance to vented air flow. In one embodiment the flow resistor units39, 41 could include an inflatable balloon. In one embodiment the flowresistor units 39, 41 could be configured to vent to atmospheresubsequent to the generation of a predetermined pressure, for example, apressure which exceeds the opening pressure for the paranasal sinusostia 5 and the tubal ostia 7. With this configuration, following thedevelopment of a pressure exceeding the opening pressure for theparanasal sinus ostia 5 and the tubal ostia 7, the flow resistancegradually decreases and the air flow increases. This pressure and flowregime can promote the deposition of airborne particles in the nasalairway 1. Furthermore, this pressure and flow regime ensures thatairborne particles are flushed out of the nasal airway 1 before theprocedure is terminated, thereby preventing airborne particles, whichcould subsequently be inhaled, from remaining in the nasal airway 1.

The delivery device 11 further comprises first and second flow meters43, 45 which are disposed in respective ones of the flow channels 25, 27of the first and second nosepiece units 17, 19 for detecting the flowrate of the flow therethrough. In this embodiment the flow meters 43, 45are disposed in the respective ones of the flow channels 25, 27 of thenosepiece units 17, 19 intermediate the respective nosepiece 21, 23 andthe respective valve 35, 37.

The delivery device 11 further comprises first and second pressuresensors 47, 49 which are disposed in respective ones of the flowchannels 25, 27 of the first and second nosepiece units 17, 19 fordetecting the pressure therein. In this embodiment the pressure sensors47, 49 are disposed in the respective ones of the flow channels 25, 27of the nosepiece units 17, 19 intermediate the respective nosepiece 21,23 and the respective valve 35, 37.

The delivery device 11 further comprises a control unit 51 forcontrolling the operation thereof. The control unit 51 is operablyconnected to the first and second substance supply units 13, 15, thefirst and second valves 35, 37 of the valve unit, the first and secondflow meters 43, 45, and the first and second pressure sensors 47, 49,whereby the first and second substance supply units 13, 15 can beactuated in response to one or both of detected pressures and flowrates.

Operation of the delivery device 11 will now be described hereinbelow.

Firstly, as illustrated in FIG. 2(a), the nosepieces 21, 23 of thenosepiece units 17, 19 are fitted to the respective nostrils of asubject and the mouthpiece 31 is gripped in the lips of the subject.With this configuration, the delivery device 11 provides for three-pointfixation, and thereby ensures reliable repeated delivery to the nasalcavities 2, 3 of a subject.

When first taking the delivery device 11, one of the valves 35, 37 ofthe valve unit, in this embodiment the first valve 35, is in thedelivery position such that the gas supply channel 33 and the respectivesubstance supply unit 13 are in fluid communication with the respectivenosepiece 21, and the other of the valves 35, 37 of the valve unit, inthis embodiment the second valve 37, is in the venting position such asto vent the other nosepiece 23.

As illustrated in FIG. 2(b), the subject then begins to exhale throughthe mouthpiece 31, which exhalation acts to close the oropharyngealvelum of the subject and increase the pressure in the nasal airway 1 bythe introduction of exhaled air from the exhalation breath thereinto,with the second flow resistor unit 41 providing a flow resistance to theexhaled air flow.

In one mode of operation, the delivery device 11 is configured to beactuated on the generation of a predetermined actuation pressure. In oneembodiment the first pressure sensor 43 is utilized to detect theactuation pressure. In another embodiment the second pressure sensor 45is utilized to detect the actuation pressure. On detection of theactuation pressure, the control unit 51 acts to actuate the firstsubstance supply unit 13 to supply a metered dose of substance, whichsubstance is entrained by the exhalation breath of the subject.

In another mode of operation, the delivery device 11 is configured to beactuated on the generation of a predetermined flow rate. In oneembodiment the first flow meter 47 is utilized to detect the actuationflow rate. In another embodiment the second flow meter 49 is utilized todetect the actuation flow rate. On detection of the actuation flow rate,the control unit 51 acts to actuate the first substance supply unit 13to deliver a metered dose of substance, which substance is entrained bythe exhalation breath of the subject.

Following actuation of the first substance supply unit 13, asillustrated in FIG. 2(c), the valve unit is then re-configured by thecontrol unit 51 such that the first valve 35 is moved to the ventingposition to vent the nosepiece 21 of the first nosepiece unit 17, andthe second valve 37 is moved to the delivery position such that the gassupply channel 33 and the second substance supply unit 15 are in fluidcommunication with the nosepiece 23 of the second nosepiece unit 19.

In one mode of operation, the valve unit is re-configured on detectionof a predetermined re-configuration pressure. In one embodiment thefirst pressure sensor 43 is utilized to detect the re-configurationpressure. In another embodiment the second pressure sensor 45 isutilized to detect the re-configuration pressure. On detection of there-configuration pressure, the control unit 51 acts to actuate thesecond substance supply unit 15 to supply a metered dose of substance,which substance is entrained by the exhalation breath of the subject.

In another mode of operation, the delivery device 11 is configured to beactuated on the detection of a predetermined reconfiguration flowvolume. In one embodiment the first flow meter 47 is utilized to detectthe re-configuration flow volume. In another embodiment the second flowmeter 49 is utilized to detect the re-configuration flow volume. Ondetection of the re-configuration flow volume, the control unit 51 actsto actuate the second substance supply unit 15 to deliver a metered doseof substance, which substance is entrained by the exhalation breath ofthe subject.

In a further mode of operation, the delivery device 11 is configured tobe actuated on the elapse of a predetermined period of time followingthe actuation of the first substance supply unit 13. On the elapse ofthe predetermined period of time, the control unit 51 acts to actuatethe second substance supply unit 15 to deliver a metered dose ofsubstance, which substance is entrained by the exhalation breath of thesubject.

Following actuation of the second substance supply unit 15, the valveunit is then re-configured to the original configuration by the controlunit 51 such that the first valve 35 is moved to the delivery positionin which the gas supply channel 33 and the first substance supply unit13 are in fluid communication with the nosepiece 21 of the firstnosepiece unit 17, and the second valve 37 is moved to the ventingposition such as to vent the nosepiece 23 of the second nosepiece unit19.

In one mode of operation, the valve unit is re-configured on detectionof a predetermined re-configuration pressure. In one embodiment thefirst pressure sensor 43 is utilized to detect the re-configurationpressure. In another embodiment the second pressure sensor 45 isutilized to detect the re-configuration pressure.

In another mode of operation, the valve unit is re-configured ondetection of a predetermined re-configuration flow volume. In oneembodiment the first flow meter 47 is utilized to detect thereconfiguration flow volume. In another embodiment the second flow meter49 is utilized to detect the re-configuration flow volume.

In a further mode of operation, the valve unit is re-configured on theelapse of a predetermined period of time following the actuation of thesecond substance supply unit 15.

In this way, the delivery device 11 provides for the successive deliveryof substance through each of the nostrils of the subject, which deliveryis advantageous, both in terms of compliance and, particularly, indelivering substance to targeted posterior regions of the nasal airway1.

In another embodiment the delivery device 11 could be configured suchthat the valve unit is re-configured more than twice in each operation,such as to provide for the repeated delivery of substance to alternateones of the nostrils of the subject in each operation of the deliverydevice 11.

FIGS. 3(a) to (c) illustrate a nasal delivery device 11 in accordancewith a second embodiment of the present invention.

The delivery device 11 of this embodiment is very similar to thedelivery device 11 of the above-described first embodiment, and thus, inorder to avoid unnecessary duplication of description, only thedifferences will be described in detail, with like reference signsdesignating like parts.

The delivery device 11 of this embodiment differs from that of theabove-described first embodiment in further comprising an exhalationbreath actuatable gas supply unit 53 which is fluidly connected to thegas supply channel 33 for delivering a gas flow thereto and operablyconnected to the control unit 51, and in that the mouthpiece 31 is influid communication with the gas supply unit 53 and not the gas supplychannel 33, whereby a gas flow is delivered by the gas supply unit 53 inresponse to exhalation by a subject into the mouthpiece 31.

The gas supply unit 53 includes a trigger mechanism 55 for actuating thesame in response to exhalation by the subject, with the triggermechanism 55 being operably coupled to the mouthpiece 31 such as to beactuated by the exhalation breath of the subject. In this embodiment thetrigger mechanism 55 comprises a pressure sensor for actuating the gassupply unit 53 in response to the detection of a predetermined actuationpressure. In another embodiment the trigger mechanism 55 could comprisea flow meter for actuating the gas supply unit 53 in response to thedetection of a predetermined flow rate.

In this embodiment the mouthpiece 31 includes a diaphragm which is actedupon by the exhalation breath of the subject to actuate the triggermechanism 55 on the generation of the predetermined actuation pressure.With this configuration, where the mouthpiece 31 is disposable, no partof the delivery device 11, other than the disposable mouthpiece 31, isexposed to the exhalation breath of the subject, and the delivery device11 can be used to deliver substance to many subjects, such as in massimmunization or mass vaccination, without the risk ofcross-contamination.

Operation of the delivery device 11 is the same as for theabove-described first embodiment, with a gas flow being provided by thegas supply unit 53 instead of being developed by the exhalation breathof the subject.

In one embodiment the gas supply unit 53 is configured to deliver a gasflow at such a flow rate as to develop a predetermined pressure in thenasal airway 1.

In another embodiment the gas supply unit 53 could be configured todeliver a gas flow which has an alternating flow and is such as todevelop an alternating pressure within the nasal airway 1. By cyclingthe pressure within the nasal airway 1, improved delivery of substanceto the paranasal sinuses 6 and the tuba auditiva 8 and the middle ears 9can be achieved. In one embodiment the delivery device 11 can beconfigured to provide for delivery of substance through only one nostrilof the subject.

In a further embodiment, at least one of the first and second flowresistors 39, 41 could comprise an expandable chamber, such as aninflatable balloon, and the gas supply unit 53 could be configuredalternately to deliver and withdraw a volume of gas through the nasalairway 1 from either one or alternately both of the nostrils of thesubject, which delivery and withdrawal would be such as to cause avolume of gas which entaains substance to be flushed repeatedly throughthe nasal airway 1 in opposite directions. Repeatedly flushing a volumeof gas entraining substance in alternate directions through the nasalairway 1 would provide for improved delivery of substance. In oneembodiment the delivery device 11 can be configured to provide fordelivery of substance through only one nostril of the subject.

FIGS. 4(a) to (c) illustrate a nasal delivery device 111 in accordancewith a third embodiment of the present invention.

The delivery device 111 comprises a substance supply unit 113 forsupplying a metered dose of substance. In preferred embodiments thesubstance comprises a medicament, especially systemic or topicalpharmaceuticals, or a vaccine.

In this embodiment the substance supply unit 113 comprises a nebulizerwhich delivers a metered dose of substance, here continuously as anaerosol spray, on actuation thereof.

The delivery device 111 further comprises first and second nosepieceunits 117, 119 for fitting to respective ones of the nostrils of asubject. In this embodiment the nosepiece units 117, 119 each comprise anosepiece 121, 123 for fitting to respective ones of the nostrils of asubject and a flow channel 125, 127 which fluidly connects therespective one of the nosepieces 121, 123 to the substance supply unit113. In this embodiment the nosepieces 121, 123 are replaceableelements.

The delivery device 111 further comprises a mouthpiece 131 which isgripped by the lips of a subject and through which the subject exhales.In this embodiment the mouthpiece 131 is a replaceable element. In apreferred embodiment the nosepieces 121, 123 and the mouthpiece 131 areintegrally formed as a single element such as to allow for replacementafter use. In this way, the delivery device 111 can be used with manydifferent subjects, for example, in mass immunization or massvaccination, and yet avoid the possibility of cross-contamination fromsubject to subject.

The delivery device 111 further comprises a gas supply channel 133 whichfluidly connects the substance supply unit 113 and the mouthpiece 131.

The delivery device 111 further comprises a valve unit which comprisesfirst and second valves 135, 137 which are disposed in respective onesof the flow channels 125, 127 of the first and second nosepiece units117, 119 such as to provide for the selective communication of one ofthe nosepieces 121, 123 with the substance supply unit 113 andmouthpiece 131, and the venting of the other of the nosepieces 121, 123to atmosphere. In this embodiment the valves 135, 137 areelectrically-operated valves.

Each of the valves 135, 137 comprises a first port which is fluidlyconnected to the respective nosepiece 121, 123, a second port which isfluidly connected to the substance supply unit 113, and a third portwhich vents to atmosphere. Each of the valves 135, 137 is operablebetween a first, delivery position in which the first and second portsthereof are open and the third port thereof is closed, whereby substancecan be delivered by the substance supply unit 113 and entrained by theexhalation breath of a subject, and a second, venting position in whichthe first and third ports thereof are open and the second port thereofis closed, whereby the exhalation breath of a subject which has beendriven through the nasal airway 1 of the subject is vented toatmosphere.

The delivery device 111 further comprises first and second flow resistorunits 139, 141 for providing a flow resistance to vented air flow whichare fluidly connected to respective ones of the third ports of thevalves 135, 137. In one embodiment the flow resistor units 139, 141 caneach include a filter for preventing the escape of substance.

In this embodiment the flow resistor units 139, 141 each include a flowresistor of fixed flow resistance for providing a fixed flow resistanceto vented air flow.

In another embodiment the flow resistor units 139, 141 could include aprogressive flow resistor for providing a progressively increasing flowresistance to vented air flow. In one embodiment the flow resistor units139, 141 could include an inflatable balloon. In one embodiment the flowresistor units 139, 141 could be configured to vent to atmospheresubsequent to the generation of a predetermined pressure, for example, apressure which exceeds the opening pressure for the paranasal sinusostia 5 and the tubal ostia 7. With this configuration, following thedevelopment of a pressure exceeding the opening pressure for theparanasal sinus ostia 5 and the tubal ostia 7, the flow resistancegradually decreases and the air flow increases. This pressure and flowregime can promote the deposition of airborne particles in the nasalairway 1. Furthermore, this pressure and flow regime ensures thatairborne particles are flushed out of the nasal airway 1 before theprocedure is terminated, thereby preventing airborne particles, whichcould subsequently be inhaled, from remaining in the nasal airway 1.

The delivery device 111 further comprises first and second flow meters143, 145 which are disposed in respective ones of the flow channels 125,127 of the first and second nosepiece units 117, 119 for detecting theflow rate of the flow therethrough. In this embodiment the flow meters143, 145 are disposed in the respective ones of the flow channels 125,127 of the nosepiece units 117, 119 intermediate the respectivenosepiece 121, 123 and the respective valve 135, 137.

The delivery device 111 further comprises first and second pressuresensors 147, 149 which are disposed in respective ones of the flowchannels 125, 127 of the first and second nosepiece units 117, 119 fordetecting the pressure therein. In this embodiment the pressure sensors147, 149 are disposed in the respective ones of the flow channels 125,127 of the nosepiece units 117, 119 intermediate the respectivenosepiece 121, 123 and the respective valve 135, 137.

The delivery device 111 further comprises a control unit 151 forcontrolling the operation thereof. The control unit 151 is operablyconnected to the substance supply unit 113, the first and second valves135, 137 of the valve unit, the first and second flow meters 143, 145,and the first and second pressure sensors 147, 149, whereby thesubstance supply unit 113 can be actuated in response to one or both ofdetected pressures and flow rates.

Operation of the delivery device 111 will now be described hereinbelow.

Firstly, as illustrated in FIG. 4(a), the nosepieces 121, 123 of thenosepiece units 117, 119 are fitted to the respective nostrils of asubject and the mouthpiece 131 is gripped in the lips of the subject.With this configuration, the delivery device 111 provides forthree-point fixation, and thereby ensures reliable repeated delivery tothe nasal cavities 2, 3 of a subject.

When first taking the delivery device 111, one of the valves 135, 137 ofthe valve unit, in this embodiment the first valve 135, is in thedelivery position such that the substance supply unit 113 is in fluidcommunication with the nosepiece 121 of the first nosepiece unit 117,and the other of the valves 135, 137 of the valve unit, in thisembodiment the second valve 137, is in the venting position such as tovent the nosepiece 123 of the second nosepiece unit 119.

As illustrated in FIG. 4(b), the subject then begins to exhale throughthe mouthpiece 131, which exhalation acts to close the oropharyngealvelum of the subject and increase the pressure in the nasal airway 1 bythe introduction of exhaled air from the exhalation breath thereinto,with the second flow resistor unit 141 providing a flow resistance tothe exhaled air flow.

In one mode of operation, the delivery device 111 is configured to beactuated on the generation of a predetermined actuation pressure. In oneembodiment the first pressure sensor 143 is utilized to detect theactuation pressure. In another embodiment the second pressure sensor 145is utilized to detect the actuation pressure. On detection of theactuation pressure, the control unit 151 acts to actuate the substancesupply unit 113 to commence delivery of a metered dose of substance,which substance is entrained by the exhalation breath of the subject.

In another mode of operation, the delivery device 111 is configured tobe actuated on the generation of a predetermined flow rate. In oneembodiment the first flow meter 147 is utilized to detect the actuationflow rate. In another embodiment the second flow meter 149 is utilizedto detect the actuation flow rate. On detection of the actuation flowrate, the control unit 151 acts to actuate the substance supply unit 113to commence delivery of a metered dose of substance, which substance isentrained by the exhalation breath of the subject.

Following actuation of the substance supply unit 113, the valve unitremains in the one configuration for a predetermined period of time, inthis embodiment for half of the time period required for the delivery ofa predetermined metered dose of substance by the substance supply unit113.

Following the elapse of the predetermined period of time, as illustratedin FIG. 4(c), the valve unit is then re-configured by the control unit151 such that the first valve 135 is moved to the venting position tovent the nosepiece 121 of the first nosepiece unit 117, and the secondvalve 137 is moved to the delivery position such that the substancesupply unit 113 is in fluid communication with the nosepiece 123 of thesecond nosepiece unit 119.

In this way, the delivery device 111 provides for the successivedelivery of substance through each of the nostrils of the subject, whichdelivery is advantageous, both in terms of compliance and, particularly,in delivering substance to targeted posterior regions of the nasalairway 1.

In another embodiment the delivery device 111 could be configured suchthat the valve unit is re-configured more than twice in each operation,such as to provide for the repeated delivery of substance to alternateones of the nostrils of the subject in each operation of the deliverydevice 111. In this embodiment this repeated alternation of the deliverynostril is achieved by directing the exhalation breath of a subject toalternate ones of the nostrils of the subject.

In alternative embodiments the substance supply unit 113 could comprisean aerosol canister for delivering a metered volume of a propellant,preferably a hydrofluoroalkane (HFA) propellant or the like, containingsubstance, either as a suspension or solution, a mechanical deliverypump, in particular a liquid delivery pump or a powder delivery pump,which delivers a metered dose of substance on actuation thereof, or adry powder delivery unit which delivers a metered dose of substance, asa dry powder, on actuation thereof. These substance supply units 113 areprimed, in one embodiment by loading a biasing element, and include arelease mechanism, in this embodiment electrically-operated, which, whentriggered, releases the biasing element and actuates the substancesupply unit 113 to deliver a metered dose of substance. In suchembodiments the substance supply unit 113 can be actuated for eachalternation of the valve unit.

FIGS. 5(a) to (c) illustrate a nasal delivery device 111 in accordancewith a fourth embodiment of the present invention.

The delivery device 111 of this embodiment is very similar to thedelivery device 111 of the above-described third embodiment, and thus,in order to avoid unnecessary duplication of description, only thedifferences will be described in detail, with like reference signsdesignating like parts

The delivery device 111 of this embodiment differs from that of theabove-described third embodiment in further comprising an exhalationbreath actuatable gas supply unit 153 which is fluidly connected to thegas supply channel 133 for delivering a gas flow thereto and operablyconnected to the control unit 151, and in that the mouthpiece 131 is influid communication with the gas supply unit 153 and not the gas supplychannel 133, whereby a gas flow is delivered by the gas supply unit 153in response to exhalation through the mouthpiece 131.

The gas supply unit 153 includes a trigger mechanism 155 for actuatingthe same in response to exhalation by the subject, with the triggermechanism 155 being operably coupled to the mouthpiece 131 such as to beactuated by the exhalation breath of the subject. In this embodiment thetrigger mechanism 155 comprises a pressure sensor for actuating the gassupply unit 153 in response to the detection of a predeterminedactuation pressure. In another embodiment the trigger mechanism 155could comprise a flow meter for actuating the gas supply unit 153 inresponse to the detection of a predetermined flow rate.

In this embodiment the mouthpiece 131 includes a diaphragm which isacted upon by the exhalation breath of the subject to actuate thetrigger mechanism 155 on the generation of the predetermined actuationpressure. With this configuration, where the mouthpiece 131 isdisposable, no part of the delivery device 111, other than thedisposable mouthpiece 131, is exposed to the exhalation breath of thesubject, and the delivery device 111 can be used to deliver substance tomany subjects, such as in mass immunization or mass vaccination, withoutthe risk of cross-contamination.

Operation of the delivery device 111 is the same as for theabove-described third embodiment, with a gas flow being provided by thegas supply unit 153 instead of being developed by the exhalation breathof the subject.

In one embodiment the gas supply unit 153 is configured to deliver a gasflow at such a flow rate as to develop a predetermined pressure in thenasal airway 1.

In another embodiment the gas supply unit 153 could be configured todeliver a gas flow which has an alternating flow and is such as todevelop an alternating pressure within the nasal airway 1. By cyclingthe pressure within the nasal airway 1, improved delivery of substanceto the paranasal sinuses 6 and the tuba auditiva 8 and the middle ears 9can be achieved. In one embodiment the delivery device 111 can beconfigured to provide for delivery of substance through only one nostrilof the subject.

In a further embodiment, at least one of the first and second flowresistors 139, 141 could comprise an expandable chamber, such as aninflatable balloon, and the gas supply unit 153 could be configuredalternately to deliver and withdraw a volume of gas through the nasalairway 1 from either one or alternately both of the nostrils of thesubject, which delivery and withdrawal would be such as to cause avolume of gas which entrains substance to be flushed repeatedly throughthe nasal airway 1 in opposite directions. Repeatedly flushing a volumeof gas entraining substance in alternate directions through the nasalairway 1 would provide for improved delivery of substance. In oneembodiment the delivery device 111 can be configured to provide fordelivery of substance through only one nostril of the subject.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

In the described embodiments the mouthpieces 31, 131 are configured tobe gripped in the lips of a subject. In alternative embodiments themouthpieces 31, 131 could be configured to be gripped by the teeth of asubject and sealed by the lips of the subject. In preferred embodimentsthe mouthpieces 31, 131 could be specifically configured to have one orboth of a shape or geometry which allows the delivery devices to begripped repeatedly in the same position, thereby providing for therespective nosepieces 21, 23, 121, 123 to be reliably inserted in thesame position in the nasal cavities 2, 3.

In preferred embodiments the delivery devices 11, 111 are configured todeliver substance through one nostril of a subject at such a pressure asto flow around the posterior margin of the nasal septum 4 and out of theother nostril of the subject, thereby achieving bi-directional deliverythrough the nasal cavities 2, 3 as disclosed in WO-A-00/51672. Inalternative embodiments the delivery devices 11, 111 can be configuredto deliver substance at a reduced pressure which is not sufficient toachieve bi-directional delivery through the nasal cavities 2, 3.

1. A nasal delivery device for delivering substance to a nasal airway ofa subject, comprising: first and second nosepiece units, each includinga nosepiece for fitting to respective nostrils of a subject; at leastone substance supply unit for supplying substance for delivery to thenasal airway of the subject; and a valve unit for selectively fluidlyconnecting the at least one substance supply unit alternately torespective ones of the nosepiece units.
 2. The delivery device of claim1, further comprising: a mouthpiece through which the subject in useexhales.
 3. The delivery device of claim 1, further comprising: a gassupply channel for supplying a gas flow for entraining substancesupplied by the at least one substance supply unit.
 4. The deliverydevice of claim 3, further comprising a mouthpiece through which thesubject in use exhales, and wherein the mouthpiece is fluidly connectedto the gas supply channel, whereby the gas flow is an air flow developedby an exhalation breath of the subject.
 5. The delivery device of claim3, further comprising: a gas supply unit which is fluidly connected tothe gas supply channel for delivering a gas flow through the gas supplychannel.
 6. The delivery device of claim 5, further comprising amouthpiece through which the subject in use exhales, and wherein the gassupply unit is an exhalation breath actuatable unit which is fluidlyconnected to the mouthpiece such as to be actuated on exhalation by thesubject.
 7. The delivery device of claim 3, wherein the valve unit isconfigured alternately fluidly to connect one of the nosepiece units tothe at least one substance supply unit and vent the other of thenosepiece units, such that, where the gas flow is at a driving pressurewhich is such as to cause the gas flow to flow around the posteriormargin of the nasal septum and through the nasal airway, the gas flowdelivered through the one nosepiece unit is vented through the othernosepiece unit.
 8. The delivery device of claim 7, further comprising:at least one flow resistor to which the other nosepiece unit is vented.9. The delivery device of claim 8, wherein the flow resistor has a fixedflow resistance for providing a fixed flow resistance to the gas flow.10. The delivery device of claim 8, wherein the flow resistor is aprogressive resistor for progressively providing an increasing flowresistance to the gas flow.
 11. The delivery device of claim 10, whereinthe progressive resistor comprises an expandable member which provides aprogressively increasing resistance to the gas flow.
 12. The deliverydevice of claim 1, further comprising: a control unit for controllingthe valve unit such as to provide for alternate delivery of substancethrough respective ones of the first and second nosepiece units.
 13. Thedelivery device of claim 1, comprising: a single substance supply unitfor supplying substance for delivery alternately to respective ones ofthe first and second nosepiece units.
 14. The delivery device of claim1, comprising: first and second substance supply units for supplyingsubstance for delivery to respective ones of the first and secondnosepiece units.
 15. The delivery device of claim 1, wherein the valveunit comprises first and second valves, each being fluidly connected toa respective one of the first and second nosepiece units.
 16. A methodof delivering substance to a nasal airway of a subject, comprising thesteps of: fitting first and second nosepiece units to respectivenostrils of a subject; and delivering substance alternately throughrespective ones of the nosepiece units.
 17. The method of claim 16,further comprising the step of: exhaling through a mouthpiece duringdelivery of substance.
 18. The method of claim 17, wherein substance isdelivered in a gas flow.
 19. The method of claim 18, wherein the gasflow is an air flow developed by an exhalation breath of the subject.20. The method of claim 18, wherein the gas flow is a gas flow separateto an exhalation breath of the subject.
 21. The method of any of claim18, wherein substance is delivered alternately to the nosepiece unitsand the other of the nosepiece units is vented, such that, where the gasflow is at a driving pressure which is such as to cause the gas flow toflow around the posterior margin of the nasal septum and through thenasal airway, the gas flow delivered through the one nosepiece unit isvented through the other nosepiece unit.
 22. The method of claim 21,wherein the gas flow is vented through a flow resistor.
 23. The methodof claim 22, wherein the flow resistor has a fixed flow resistance andprovides a fixed flow resistance to the gas flow.
 24. The method ofclaim 22, wherein the flow resistor is a progressive resistor whichprovides a progressively increasing flow resistance to the gas flow. 25.The method of claim 24, wherein the progressive resistor comprises anexpandable member which provides a progressively increasing resistanceto the gas flow.
 26. The method of claim 16, wherein substance issupplied from a single substance supply unit.
 27. The method of claim16, wherein substance is supplied to the first and second nosepieceunits from respective ones of first and second substance supply units.28. A nasal delivery device for delivering substance to a nasal airwayof a subject, comprising: a mouthpiece through which a subject in useexhales; at least one delivery unit for delivering substance to a nasalairway of the subject on exhalation by the subject; and a gas supplyunit for cycling a pressure in the nasal airway of the subject onexhalation by the subject.
 29. The delivery device of claim 28, whereinthe gas supply unit is configured to provide an alternating pressure inthe nasal airway of the subject.
 30. The delivery device of claim 28,wherein the gas supply unit is an exhalation breath actuatable unitwhich is fluidly connected to the mouthpiece such as to be actuated onexhalation by the subject.
 31. A method of delivering substance to anasal airway of a subject, comprising the steps of: delivering substanceto a nasal airway of a subject; and applying a varying pressure in thenasal airway of the subject.
 32. The method of claim 31, wherein thestep of applying a varying pressure in the nasal airway of the subjectcomprises the step of: cycling the pressure in the nasal airway of thesubject.
 33. The method of claim 32, wherein the step of applying avarying pressure in the nasal airway of the subject comprises the stepof: alternating the pressure in the nasal airway of the subject.
 34. Themethod of claim 31, further comprising the step of: exhaling through amouthpiece during delivery of substance.
 35. A nasal delivery device fordelivering substance to a nasal airway of a subject, comprising: amouthpiece through which a subject in use exhales; at least one deliveryunit for delivering substance to a nasal airway of the subject; and agas supply unit for alternately delivering and withdrawing a volume ofgas through the nasal airway of the subject such as to cause entrainedsubstance to be flushed in alternate directions therethrough.
 36. Amethod of delivering substance to a nasal airway of a subject,comprising the steps of: delivering substance to a nasal airway of asubject; and alternately delivering and withdrawing a volume of gasthrough the nasal airway of the subject such as to cause entrainedsubstance to be flushed in alternate directions therethrough.
 37. Themethod of claim 36, further comprising the step of: exhaling through amouthpiece during delivery of substance.
 38. An interface member forattachment to a nasal delivery device, comprising, as an integralelement, at least one nosepiece for fitting to a nostril of a subjectand a mouthpiece through which the subject in use exhales, wherein themouthpiece includes a flexible member which is deflectable on exhalationinto the mouthpiece.
 39. The interface member of claim 38, comprisingfirst and second nosepieces for fitting to respective nostrils of asubject.
 40. The interface member of claim 38, where being a disposableelement.
 41. The interface member of claim 38, wherein the mouthpiececomprises a tubular section through which the subject in use exhales.42. The interface member of claim 38, wherein the mouthpiece comprises acavity into which the subject in use exhales, with a part of the cavitybeing defined by the flexible member.
 43. The interface member of claim38, wherein the flexible member comprises a resilient member.